Is NOTCH1 p.Val776= (c.2328G>A) pathogenic?

NOTCH1 p.Val776= (c.2328G>A) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-21). Very rare (popmax 0.00534%, afr); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Val776= (c.2328G>A)?

NOTCH1 p.Val776= (c.2328G>A) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Val776= (c.2328G>A) in the general population?

NOTCH1 p.Val776= (c.2328G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

NOTCH1 p.Val776=

c.2328G>A · rs753328797 · VCV2039732

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.34	GERP -3, phastCons 0.97
Overall
CADD	6.836	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,948 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,612,834 alleles · very rare exomes 3/1,460,566 · genomes 2/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,737
Remaining individualsnot grpmax-eligible	0.0016%	62,470

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NOTCH1
Protein: p.Val776=
Coding: c.2328G>A
MANE Select: NM_017617
dbSNP: rs753328797
Type: single nucleotide variant
Location: chr9:136513417 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 776: the egf-like 20 domain; a β-strand

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

NOTCH1 p.Val776Gly Uncertain significance ★ ⚠ same residue
NOTCH1 p.Val776Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 p.Val776Met Benign ★ same residue
NOTCH1 p.Val776del Uncertain significance ★ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.3511-1G>A Likely pathogenic ★★ same condition
NOTCH1 p.Arg1107Ter Pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/notch1-p-val776 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown